ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.80371dup (p.Asp26791fs)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002344679 SCV002646788 likely pathogenic Cardiovascular phenotype 2020-11-12 criteria provided, single submitter clinical testing The c.53176dupG variant, located in coding exon 153 of the TTN gene, results from a duplication of G at nucleotide position 53176, causing a translational frameshift with a predicted alternate stop codon (p.D17726Gfs*15). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). As such, this alteration is classified as likely pathogenic.

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